This goal of this project is to develop an innovative process for treating patients with Waldenstrm's macroglobulinemia by suppressing the production of IgM. Waldenstrm's macroglobulinemia is incurable and fatal. The manifestations of this disease that are due to high concentrations of monoclonal IgM are hyperviscosity with headache, fatigue, impaired cognition, confusion, and stroke, peripheral neuropathy and systemic amyloidosis which may result in death. We hypothesize that the production of IgM by malignant plasma cells can be stopped by using RNA interference which can be administered systemically and specifically targets the plasma cells which produce IgM. This will be accomplished by using an innovative recombinant fusion protein that targets the malignant plasma cells by its antigen binding portion and delivers the RNA interference into the plasma cells by natural internalization. The fusion protein consists of an antibody fragment for cell specific targeting and a modified version of human protamine for carrying the short interfering RNA to the tissue and into the plasma cells. This treatment will be tested in a mouse model of Waldenstrm's macroglobulinemia. Our Specific Aims are 1. Create fusion proteins that maintain cell binding, are internalized by the malignant plasma cells and then inhibit IgM production; 2. Optimize the functional behavior of the fusion proteins; 3. Demonstrate the in vivo anti- malignant behavior of the fusion proteins. Our method will overcome the major impediment to the use of RNA interference systemically, i.e. inability of present methods to deliver RNA interference by systemic administration with specific targeted cellular and tissue delivery. Our Phase II objectives will include optimization of dosage and assessment of side effects using an animal model of this disease.